A new study published in Nature Communications on January 29, 2025, sheds light on the potential of DOPA decarboxylase (DDC) as a biomarker for Lewy body disorders (LBDs), including dementia with Lewy bodies (DLB) and Parkinson’s disease (PD). While cerebrospinal fluid (CSF) levels of DDC have previously shown promise in identifying these conditions, the research highlights complexities regarding its use in blood-based testing and the significant influence of dopaminergic treatment on its levels.
Researchers evaluated plasma DDC levels using a proximity extension assay across three independent cohorts: an autopsy-confirmed group (n=71), a large multicenter cross-dementia cohort (n=1498), and a longitudinal cohort with detailed treatment information (n=66, with a median follow-up of 4 years). The study found that, unlike CSF DDC, plasma DDC levels were not consistently altered between different LBDs, other dementia types, or healthy controls in individuals not receiving treatment.
Interestingly, the research revealed a significant increase in plasma DDC levels over time in patients with Parkinson’s disease. This increase was strongly associated with higher dosages of dopaminergic medication, the primary treatment for PD. This finding underscores the critical need to consider treatment effects when interpreting plasma DDC levels.
“This emphasizes the need to consider treatment effect when analyzing plasma DDC,” the study authors wrote. They suggest that, in contrast to CSF DDC, plasma DDC may have limited utility as a diagnostic biomarker for LBDs. However, they propose it could be valuable for monitoring treatment response.
The study builds upon previous research establishing DDC as a potential biomarker for Parkinsonian disorders. A study published in Nature in September 2023 demonstrated that CSF levels of DDC could accurately identify patients with LBD, and even detect preclinical stages of the disease in individuals with positive alpha-synuclein seed amplification assays. That research also indicated that higher DDC levels were associated with worse cognitive performance.
The current investigation included detailed analysis of patient cohorts from multiple centers, including the Alzheimer’s Disease CSF biobank (ADC), the Danish Dementia Biobank (DDBB/BMDB), the University of Perugia, and Yonsei University Health System (YUHS). Researchers utilized standardized diagnostic criteria for LBD, PD, mild cognitive impairment, and Alzheimer’s disease, and confirmed diagnoses through neuropathological examination in some cases.
The study also involved rigorous analytical validation of the DDC immunoassays used, ensuring accuracy and reliability of the measurements. Researchers performed validations for lower limit of detection, precision, parallelism, dilution linearity, recovery, and sample stability, adhering to established consensus guidelines.
Immunohistochemical analysis of brainstem tissue from individuals with and without LBD further explored the distribution of DDC. These analyses were performed on postmortem tissue from the Netherlands Brain Bank and the neurobiobank of the Institute Born-Bunge of the University of Antwerp.
The findings suggest that while CSF DDC remains a promising area of investigation for LBD diagnosis, the influence of dopaminergic treatment complicates the interpretation of plasma DDC levels. Further research is needed to determine the optimal use of DDC as a biomarker, potentially focusing on its role in treatment monitoring rather than initial diagnosis. The study highlights the importance of considering medication status when evaluating DDC levels in individuals suspected of having LBD or PD.
Researchers noted that additional studies are needed to fully understand the relationship between DDC levels and disease progression, as well as to identify potential therapeutic targets based on DDC activity. The study also acknowledged the need for standardized protocols for DDC measurement to ensure comparability across different laboratories and clinical settings.
